CD154 induces p73 to overcome the resistance to apoptosis of chronic lymphocytic leukemia cells lacking functional p53.

Abstract:

:Intravenous infusion of autologous chronic lymphocytic leukemia (CLL) cells transduced with an adenovirus encoding CD40-ligand (CD154) caused rapid reductions in leukemia-cell counts and lymphnode size. We hypothesized that CD40-ligation via CD154 sensitized CLL cells to death-receptor-mediated apoptosis. We found that CD154-expressing cells induced expression of CD95 and the BH3-interacting-domain death agonist (Bid) in CLL, regardless of whether the leukemia cells had functional p53. Such treatment also induced p73, a p53-related transcription factor regulated by c-Abl kinase, and enhanced the sensitivity to fludarabine (F-ara-A) of CLL cells lacking functional p53. Transduction of CLL cells with an adenovirus encoding p73 also induced Bid and CD95 and enhanced the sensitivity to F-ara-A of p53-deficient CLL cells. However, inhibition of c-Abl with imatinib suppressed CD154-induced expression of p73, p73-induced expression of Bid and CD95, and blocked the sensitization of p53-deficient CLL cells to CD95-mediated or F-ara-A-induced apoptosis. Conversely, CLL cells transduced with an imatinib-resistant c-Abl mutant could be induced by CD154 to express p73 and Bid even when treated with imatinib. These results indicate that CD154 can sensitize leukemia cells to apoptosis via the c-Abl-dependent activation of p73 and mitigate the resistance of p53-deficient CLL cells to anticancer drug therapy.

journal_name

Blood

journal_title

Blood

authors

Dicker F,Kater AP,Prada CE,Fukuda T,Castro JE,Sun G,Wang JY,Kipps TJ

doi

10.1182/blood-2006-04-017749

subject

Has Abstract

pub_date

2006-11-15 00:00:00

pages

3450-7

issue

10

eissn

0006-4971

issn

1528-0020

pii

blood-2006-04-017749

journal_volume

108

pub_type

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